Issue 186, December 2016
www.proteinspotlight.org
the contours of heredity
Vivienne Baillie Gerritsen
Life has its shapes, and depends on all kinds of architecture. It needs a skeleton on which to hang. Blood
vessels in which to flow. A brain to house its thoughts. A heart to give it a beat. On a far smaller scale, it
needs cells to accommodate all the various components without which there would be no life in the first
place. One of the most important being: DNA. DNA itself is found within a defined structure in each of
our cells: the nucleus. Within this protective core, our genetic heritage adopts yet other variable
conformations depending on a cell’s stage in mitosis. One of these conformations is the well-known
chromosome. Chromosomes are simply highly-packed DNA, which is an ideal conformation to be in when
a cell is about to divide for instance, and chromosomes need to move around. Many different proteins
work in unison to keep chromosomes arranged in such a way. One in particular has recently proved to be
important in maintaining the shape of packed chromosomes, and is called proliferation marker protein
Ki-67.
packed very tightly, making it far easier for the
nucleus to identify chromosomes individually and
distribute them correctly into the two daughter cells
of a dividing cell. It is not dissimilar to folding
clothing items thus making it easier to identify
them one by one and tidy them away into drawers.
Chromatin-packing may sound straightforward and
perhaps even obvious, but it has taken well over a
century to come to these conclusions and
understand chromosome structure at the molecular
level.
Monarch Double Helix 210 2016, by Rafael Araujo
Courtesy of the artist
Why is it important for chromosomes to keep their
shape in the first place? In the process of cell
division, mammalian chromosomes evolve from an
untidy slack conformation – bearing resemblance to
boiled spaghetti – to the “X” conformation
characteristically used to illustrate a chromosome.
This “X” conformation is achieved when the DNA
– or chromatin – of the slack chromosome is
The German biologist Walther Flemming (18431905) was the first to observe what he termed
“chromatin” because it was the substance in the cell
nucleus that was “readily stained” under the
microscope. At the time though, no one was yet
aware of what its individual components were, i.e.
DNA and protein. Nucleic acids had indeed been
uncovered by the Swiss biologist Friedrich
Miescher (1844-1895) in the 1870s already, but the
notion of DNA as a “transforming principle” only
emerged in the early 1940s and its structure was
still to be unveiled. So, though the first half of the
20th century made huge leaps in the field of
genetics, little was known on the molecular front.
By the early 1940s, scientists knew that chromatin
was a mixture of DNA and histone proteins.
Intriguingly though, since DNA seemed to be so
monotonous from a structural point of view, the
consensus was that the histones must be the carriers
of genetic information. This notion soon shifted,
however, when the double helix structure of DNA
was reported by the American biologist James
Watson and the English physicist Francis Crick
(1916-2004) in 1953. Finally, during the 1970s and
the 1980s, the discovery and the role of what has
been called the “quantum of chromatin” was
described: the nucleosome. Made of a histone core
around which is coiled a given stretch of DNA,
nucleosomes form the structural unit of chromatin
packaging. They are responsible for its tight
packing into the shape of chromosomes, and are
therefore of great significance in gene expression.
sort of ephemeral electrostatic “exoskeleton”, a
little like a suitcase into which clothes have been
stashed for a journey. Once over, the suitcase is
opened, and the clothes released. This is precisely
what happens to the Ki-67 sheath. When cell
division has occurred, and the chromosomes have
been distributed between the two nascent cells, the
nucleolus reassembles to contain them. The Ki-67
sheath then dissolves, and the chromosomes adopt
their untidy slack spaghetti-like conformation as
they await the next cell cycle.
Proliferation marker protein Ki-67, or Ki-67, does
not help to pack DNA into chromosomes, but it
does prevent them from losing their shape. How?
KI-67 is a nuclear-binding protein in mammalian
cells. It is very large, has a very high electrical
charge and seems to exist in a long unfolded
conformation. Its structure is amphiphilic, meaning
that one side is negatively charged, while the other
is positively charged – typical features of surfaceactive agents. Ki-67 is hugely expressed during cell
division – the time when the nucleolus
disassembles to release its chromosomes and share
them equally between two nascent daughter cells. It
is precisely at this point that Ki-67 becomes
essential by forming a sort of sheath around each
mitotic chromosome making sure that everything
stays tightly packed and neatly in place.
So Ki-67 holds chromatin in a highly compacted
form while, no doubt, mediating long-range
interactions between different parts of the
chromosome. Furthermore, since each outside shell
has the same electric charge, instead of getting
hopelessly tangled, chromosomes bounce off each
other! This is a delightful example of the
biomechanical role of a protein. This said, though
essential, Ki-67 does not work on its own: at least
seventeen other proteins are known to be involved
in the process too. It could be that Ki-67 targets
these proteins to their correct sites in the process of
compaction. Time will tell. With all this in mind, it
is not surprising that Ki-67 is used as a biomarker
in the prognosis of cancer. Cell division is highly
controlled, and only certain cells should be dividing
at a given time in our body. Ki-67 can be used to
tell if the wrong cells have indeed lost control, as
can other biomarkers within the nucleolus. In this
light, inhibitors of nucleolar functions have been
shown to destroy cancer cells selectively, and
getting to know them in greater detail will help in
the never-ending fight against an affliction that kills
far too often.
A closer look at this sheath reveals a dense fuzzy
brush-like structure that runs around the contour of
each chromosome. On closer inspection, each
“hair”, so to speak, is formed by a Ki-67 protein,
whose C-terminus is attracted to chromatin while
its N-terminus prefers the cytoplasm. This creates a
Cross-references to UniProt
Proliferation marker protein Ki-67, Homo sapiens (Human) : P46013
Proliferation marker protein Ki-67, Mus musculus (Mouse) : E9PVX6
References
1.
Sobecki M., Mrouj K., Camasses A., Parisis N., Nicolas E., Llères D., Gerbe F., Prieto S., Krasinska L.,
David A., Eguren M., Birling M.-C., Urback S., Hem S., Déjardin J., Malumbres M., Jay P., Dulic V.,
Lafontaine D.L.J, Feil R., Fisher D.
The cell proliferation antigen Ki-67 organises heterochromatin
eLIFE 2016;5:e13722
PMID: 26949251
2.
Cuylen S., Blaukopf C., Politi A.Z., Müller-Reichert T., Neumann B., Poser I., Ellenberg J., Hyman A.A.,
Gerlich D.W.
Ki-67 acts as a biological surfactant to disperse mitotic chromosomes
Nature 535:308-312(2016)
PMID: 27362226
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